Using a combination of genetic strategies we have recently shown expression of the PTH4P gene to be essential for the process of tooth eruption. This finding, coupled with a pattern of expression that peaks in the epithelial layers on the coronal surface of the molars immediately prior to their scheduled eruption through the overlying bone, identifies PTHrP as the "epithelial clock" molecule that was originally proposed to regulate the timing of tooth eruption. PTHrP appears to act in this capacity by regulating both the number and distribution of osteoclasts surrounding the tooth via interaction with an unidentified intermediary cell type. Genetic models have also shown a requirement for PTHrP in the maintenance of a bone free zone around the tooth that defends against invasion and impaction, suggesting a wider role for this peptide in regulating the interface between the tooth and the surrounding bone. Our central hypothesis, therefore, proposes that the dental crypt independently provides all the basic factors required for the recruitment, formation/fusion, differentiation and functional activation of osteoclasts and regulates the deployment of these factors in a temporo-spatial pattern designed to orchestrate the process of tooth eruption. We further propose that PTHrP signals through neighboring, receptor-bearing dental follicular mesenchymal cells, which in turn act as osteoblast surrogates to induce osteoclast activation. Based on these assumptions, we propose the following: 1) that the dental follicular mesenchyme is both necessary and sufficient to mediate the induction of osteoclastic bone resorption in response to PTHrP, 2) that PTHrP is required for a) the continuous growth of rodent incisors, b) the extension of both incisor and molar roots, and c) the apparent protective function of PTHrP expression in the outer enamel epithelium during tooth development, and 3) that the actions of PTHrP on osteoclastic bone resorption are mediated by an as yet unidentified downstream factor that is produced by PTHrP-stimulated dental follicle cells.